PROJECT SUMMARY Background: Vaccines against human papillomavirus (HPV) are highly efficacious (>95%) for the prevention of precancerous high-grade cervical lesions (HGCL) and have been available in the US since 2006. Current recommendations are to routinely immunize adolescents at ages 11?12 years with three doses over six months. Nearly 10 years after the introduction of the first HPV vaccine, important questions remain about the extent to which these vaccines are realizing their full potential. The real-world effectiveness of HPV vaccines as used in clinical practice likely is quite different from their efficacy in pre-licensure clinical trials. If the vaccine is given after the recommended ages for routine administration, it may be less effective since the vaccine has no therapeutic effect and many older adolescents will have already been infected with HPV. In the US, there are substantial delays in completing immunization with HPV vaccine; only 26% of females have received all three doses by age 13 years. Many clinicians are not aware that the vaccine's effectiveness is likely to be dependent on age at the time of vaccination, in part because we do not currently have empirical estimates of the vaccine's effectiveness when administered at different ages. Aims and Approach: We will conduct a population-based case-control study to determine the effectiveness of HPV vaccines in preventing HGCL in real-world settings, both overall and by age at the time of immunization. The study will be conducted in New Haven County, Connecticut where there has been ongoing surveillance for HGCL, including typing of cervical specimens, since 2008. Cases will be women with newly diagnosed HGCL associated with HPV types 16 or 18 (prevented by current vaccines and responsible for ~50% of HGCL and ~70% of cervical cancers) who were age-eligible for HPV vaccine. Controls will be matched to cases by age, date of testing, and medical practice. We will interview all participants and review all medical records to determine dates of receipt of HPV vaccine. We will use conditional logistic regression to estimate the vaccine's effectiveness while controlling for potential confounders. Significance: Results of this study will provide critically needed estimates of the real-world effectiveness of HPV vaccines as they are being used in actual clinical practice. This will be the first study to provide evidence- based information about the extent to which delays in the timing of immunization affect the vaccine's effectiveness and will provide estimates of its effectiveness by age at the time of immunization. Empirical estimates that quantify the actual increased benefit of immunization at younger ages can be a potent incentive to increase the timeliness of recommendations by clinicians to immunize adolescents at ages 11?12 years and to increase acceptance by parents of immunization at these ages. Results of the proposed study will provide much needed evidence that can be used to develop strategies to more fully realize the potential benefits of HPV vaccine.